Full Text AI-95-003


NIH GUIDE, Volume 23, Number 40, November 18, 1994

RFA:  AI-95-003

P.T. 34

  Clinical Trial 

National Institute of Allergy and Infectious Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Office of Research on Women's Health

Letter of Intent Receipt Date:  January 15, 1995
Application Receipt Date:  March 21, 1995


The National Institute of Allergy and Infectious Diseases (NIAID),
the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), the National Institute of Arthritis and Musculoskeletal and
Skin Diseases (NIAMS), and the Office of Research on Women's Health
(ORWH) of the National Institutes of Health invite applications for
research into the basic mechanisms underlying new immunotherapies
being tested for the prevention and treatment of various autoimmune
diseases.  Human clinical trials of new and innovative therapies for
autoimmune disease are proceeding even though the exact mechanisms of
the interventions being tested are unknown.  This Request for
Applications (RFA) seeks studies that would expand the clinical
evaluation of these experimental treatments by incorporating basic
research on the molecular and immunologic mechanisms underlying these
immune therapies.  By augmenting the clinical investigations with
research designed to elucidate specific mechanisms of action,
assessment of clinical outcomes will be more meaningful and could
facilitate the development of future therapeutic strategies.


The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Mechanisms Underlying Immunotherapy Trials in Autoimmunity, is
related to the priority area of diabetes and chronic disabling
diseases.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No. 017-001-00474-0) or "Healthy People
2000" (Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone (202) 782-3238).


Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private institutions, such as
universities, colleges, hospitals, laboratories, units of State or
Local governments, and eligible agencies of the Federal government.
Foreign institutions are not eligible to apply for First Independent
Research Support and Transition (FIRST) (R29) awards.  Racial/ethnic
minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.


The mechanisms of support will be the individual research project
grant (R01) and the FIRST (R29) award.  The total project period for
applications submitted in response to this RFA may not exceed five
years; foreign applications may not request more than three years of
support.  Responsibility for the planning, direction, and execution
of the proposed project will be solely that of the applicant.

This RFA is a one-time solicitation.  Future competing renewal
applications will compete with all investigator-initiated
applications and will be reviewed according to customary referral and
review procedures.


The estimated funds available for the total (direct and indirect)
first-year costs of all awards made under this RFA will be $750,000
from NIAID, $250,000 from NIDDK, $250,000 from NIAMS, and $200,000
from ORWH.  In Fiscal Year 1996, the NIAID plans to fund
approximately four R01/R29s, NIDDK one R01/R29, NIAMS one R01/R29,
and ORWH one R01/R29.  The usual PHS policies governing grants
administration and management will apply.  This level of support is
dependent on the receipt of a sufficient number of applications of
high scientific merit.  Although this program is provided for in the
financial plans of the Institutes, awards pursuant to this RFA are
contingent upon the availability of funds for this purpose.  Funding
beyond the first and subsequent years of the grant will be contingent
upon satisfactory progress during the preceding years and
availability of funds.



Autoimmune diseases are a significant source of morbidity, often
severe, in the U.S. population, costing billions annually in health
care expenditures and lost productivity.  Many of these diseases,
including Systemic Lupus Erythematosus, Rheumatoid Arthritis and
Multiple Sclerosis, disproportionately affect women rather than men.
One hypothesis for the pathogenesis of these diseases is that there
is failure of the normal process of self-tolerance.  Studies of these
diseases in animal models suggest that tolerance to self antigens can
be induced by the oral or peripheral presentation of various antigens
with a reduction in the incidence of the disease.  Several
preliminary trials in humans have also suggested that these diseases
may be ameliorated or prevented with antigen based therapy.  Based on
these interesting results, clinical trials in humans have begun in
patients with Insulin-Dependent Diabetes Mellitus, Multiple
Sclerosis, and Rheumatoid Arthritis to determine if these diseases
can be prevented or treated with immunotherapy.  Other new innovative
therapies of autoimmune disease directed at modulation of the immune
system are also being tested, including treatment of Rheumatoid
Arthritis patients with monoclonal or chimeric antibodies directed
against TNF-` or adhesion molecules or non-depleting CD-4 antibodies
or administration of collagen peptides to patients with scleroderma.

Research Objectives and Scope

This RFA seeks to support hypothesis-driven basic research projects
investigating molecular and cellular mechanisms underlying changes in
the immune response and clinical outcome in patients enrolled in
large scale, funded clinical trials of the efficacy of
immunotherapies to treat or prevent autoimmune disease.  By
augmenting ongoing clinical studies, the NIH seeks to take advantage
of these unique clinical populations to gain valuable insights into
autoimmunity.  Examples of ongoing clinical trials appropriate for
studies of basic underlying mechanisms include, the Diabetes
Prevention Trial - Type 1, to test the administration of a self
antigen (insulin), either orally or subcutaneously, in preventing
development of diabetes; and clinical trials testing the oral
administration of chicken Type II collagen for the treatment of
Rheumatoid Arthritis and oral administration of myelin for the
treatment of Multiple Sclerosis.  However, basic research projects
linked to large-scale, funded human trials of other innovative
immunotherapies for the prevention/treatment of autoimmune disease
are also be appropriate for this RFA.  Studies related to clinical
trials evaluating the use of immunosuppressive drugs for the
prevention/treatment of autoimmune disease are NOT within the scope
of this RFA.

The NIH is interested in increasing understanding of the
immunological mechanisms underlying these new innovative therapies
for autoimmune disease.  The specific research approach proposed in
each application will be dependent on the particular intervention
utilized in the trial.  Examples of possible relevant hypothesis-
driven research topics include, but are not limited to, assessments
of alterations in relevant molecular and cellular aspects of the
immune response such as:

o  Evaluation of responses to disease-related and control antigens in
helper T cells, suppressor T cells, B cells, and inflammatory cells

o  Studies of disease-related antibody responses and/or disease-
related activation of other mediators of the immune and/or
inflammatory responses

o  Investigations of antigen presentation and tolerance
induction/maintenance and studies of molecular mechanisms of cell

o  Effects of immunotherapy on cell trafficking and migration and the
production and activity of the molecular mediators of relevant

Hypothesis-driven studies of cell populations whose presence or
activity correlates with activity of disease would be particularly
useful.  These examples are not intended to be all encompassing or
limiting.  Studies in animals that parallel the human clinical trials
WILL NOT be considered responsive.  Close collaboration between
clinical and basic scientists in the planning and implementation of
these research studies is highly encouraged.

NOTE:  Investigators proposing to utilize the patient populations
from clinical trials must obtain permission from the ancillary
studies committees of the appropriate trial.  Applications must
include evidence that approval has been applied for and written
approval by the appropriate Study Group of the ongoing trial for
which basic research studies are being proposed under this RFA must
be provided by the time the application is reviewed.

NOTE: Investigators interested in developing small basic research
projects ($50,000 - Direct Costs) linked to clinical trials should
look for the soon to be issued NIAMS-sponsored RFA "Small R01 Program
for Mechanisms of Immunotherapy in Rheumatic Diseases".


It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH-supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which has been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may also
provide additional relevant information concerning the policy.


Prospective applicants are asked to submit, by January 15, 1995, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address and telephone number of the
Principal Investigator, and the number and title of this RFA.
Although the letter of intent is not required, is not binding, does
not commit the sender to submit an application, and does not enter
into the review of subsequent applications, the information that it
contains allows NIAID staff to estimate the potential review workload
and to avoid conflict of interest in the review.  The letter of
intent is to be sent to Dr. Olivia Preble at the address listed under


Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 9/91).  These application forms may be
obtained from the institution's office for sponsored research or its
equivalent and from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 5333 Westbard Avenue,
Room 449, Bethesda, MD 20892, telephone (301) 710-0267.  For purposes
of identification and processing, item 2a on the face page of the
application must be marked "YES" and the RFA number and the words
typed in.

It is highly recommended that the NIAID program staff, listed under
INQUIRIES, be consulted before submitting the letter of intent and
during the early stages of preparation of the application.
Applications that do not conform to the instructions contained in PHS
398 (rev. 09/91) application kit, will be judged nonresponsive and
will be returned to the applicant.

The RFA label available in the PHS 398 must be affixed to the bottom
of the face page.  Failure to use this label could result in delayed
processing of the application such that it may not reach the review
committee in time for review.  FIRST award (R29) applications must
include at least three sealed letters of reference attached to the
face page of the original application.  FIRST applications submitted
without the required number of reference letters will be considered
incomplete and will be returned without review.

Applications must be received by March 21, 1995.  Applications
received after the receipt date will be returned without review.  The
Division of Research Grants (DRG) will not accept any application in
response to this RFA that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application.  This does not exclude the submission of substantial
revisions of an application already reviewed.  These applications
must, however, include an introduction addressing the previous

Submit a signed, typewritten original of the application, including
the checklist, and three signed, exact, single-sided photocopies, in
one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional exact copies of the grant
application and all five sets of the appendix must also be sent to
Dr. Olivia Preble at the address listed under INQUIRIES.

Applicants from institutions THAT have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or principal investigator could be included
with the application.


Upon receipt, applications will be reviewed for completeness by the
DRG and for responsiveness by NIAID staff.  Incomplete and non-
responsive applications will be returned to the applicant without
further consideration.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIAID in accordance with the review
criteria stated below.  As part of the initial merit review, a
process (triage) may be used by the initial review group in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications
received in response to the RFA.  Applications judged to be
competitive will be discussed and be assigned a priority score.
Applications determined to be non-competitive will be withdrawn from
further consideration and the principal investigator and the official
signing for the applicant organization will be promptly notified.
The second level of review will be provided by the National Advisory
Allergy and Infectious Diseases Council.

Review Criteria

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be

For foreign applications, in addition to the above criteria, the
reviewers will be asked to comment on the availability of special
opportunities for furthering research programs through the use of
unusual talent resources, populations, or environmental conditions
that are not readily available in the United States or which provide
augmentation of existing U.S. resources.

The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.


Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program priorities, and
the availability of funds.


Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

Elaine Collier, M.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A20
6003 Executive Boulevard
Bethesda, MD  20892-7640
Telephone:  (301) 496-7104
FAX:  (301) 402-2571
Email:  EC5X@NIH.GOV

Joan T. Harmon, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 5AN-18G
Bethesda, MD  20892
Telephone:  (301) 594-7565
FAX:  (301) 594-9011
Email:  joanh@dvsgate.niddk.nih.gov

Susana Serrate-Sztein, M.D.
Rheumatic Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-376
45 Center Drive MSC 650
Bethesda, MD  20892-650
Telephone:  (301) (301) 594-5032
Email:  arthrit@ep.niams.nih.gov

Direct inquiries regarding review issues, mail two copies of the
application and all five sets of appendices, and mail letter of
intent to:

Olivia T. Preble, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C19
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 496-8208
FAX:  (301) 402-2638
Email:  OP2T@NIH.GOV

Direct inquiries regarding fiscal matters to:

Ms. Jacqueline Johnson
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B26
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
Email:  JJ19E@NIH.GOV


Letter of Intent Receipt Date:  January 15, 1995
Application Receipt Date:       March 21, 1995
Scientific Review Date:         June/July 1995
Advisory Council Date:          September 1995
Earliest Award Date:            December 1995


This program is described in the Catalog of Federal Domestic
Assistance, No. 93.855, No. 93.847, and No. 93.361.  Awards will be
made under the authority of the Public Health Service Act, Title IV,
Part A, (Public Law 78-410, as amended by Public Law 99-158, 42 USC
241 and 285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free work place and promote the nonuse
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American


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